2, 4b-dimethyl-1-acetaldehydo-2-methallyl-1, 2, 3, 4, 4a, 4b, 5, 6, 7, 9, 10, 10a-dodecahydrophenanthrene-4, 7-dione and methods of preparing the same



2,4b DIMIETHYL -1- ACE'I'ALDEHYDD -2- METH- ALLYlLl,2,3,4,4a,4h,5,6,7,9,10,10a DODEC- DROPHENANTHRENE-4J-DIUNE AND METH-(PDS F PREPARWG T S Lewis H. Sarett, Princeton, N.J., George I. Poos,Philadelphia, Pa, and William F. Johns, Morton Grove, EL, assignors toMerck & (30., line, Railway, N.J., a corporation of New Jersey NoDrawing. (Iriginal application September 9, 1953, Serial No. 379,282,now Patent No. 2,837,516, dated June 3, 1958. Divided and thisapplication March 4, 1957, Serial No. 643,888

2 Claims. (Cl. 269-3403) This application is a division of Serial No.379,282, filed September 9, 1953, now Patent No. 2,837,516.

This invention relates to novel dodecahydrophenanthrene compounds, andprocesses of preparing the same. More particularly, it is concerned Witha method of forming the 5 membered D ring of the steroid molecule froman appropriately substituted dodecahydrophenanthrene compound, and Withthe new compounds so obtained. Specifically, it is concerned with anovel method of converting 2,4b-dirnethyl-1-(B,hydroxyethyl)-2-methallyl 7 ethylenedioxy1,2,3,4\,4a,4b,5,6,7,8,10,10adodecahydropl1enanthrene-4-ol to2,4b-dimethyl-7-ethylenedioxy 2 (B ketopropyl) l acetaldehydo 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one, and the process ofconverting this compound to A -3- ethylenedioxy-pregnadiene-11,20-dione,and the valuable compounds so prepared.

The preparation of valuable steroid substances by total synthesis,involving formation of the four ring sys tem, introduction of angularmethyl groups, at positions 10 and 13, and placing of desired functionalsubstituents in the ring system, presents a formidable challenge. Inaddition to these di'ificulties, the problem is further complicated bythe stereochemistry of steroidal substances. Thus, saturated steroids,with a minimum of six asymetric centers, are capable of existing in atleast sixty four stereochemical modifications. In spite of thesedifliculties, efforts have been made to prepare steroids by totalsynthesis in view of the importance and value of steroids such ascortisone, and the scarcity of row materials suitable as startingmaterials for the preparation of these important products.

It is an object of the present invention to provide a method ofpreparing steroid compounds from dodecahydrophenanthrene compounds.Another object is to provide a process for the preparation of 11-ketoprogesterone from functionally substituted dodecahydrophenanthrenecompounds.

An additional object is to provide novel dodecahydrophenanthrenecompounds which are useful as intermediates in the synthesis of ll-ketoprogesterone.

Other objects will be apparent from the detailed description of thisinvention hereinafter provided.

In accordance with the present invention, it is noW found thatderivatives of 2,4b-dimethyl-l-(B-hydroxyethyl) 2 methallyl1,2,3,4,4a,4b,5,6,7,9,10,109. dodecahydrophenanthrene4-ol-7-one whereinthe 7-keto substituent is blocked or protected by a substituentconvertible to keto by hydrolysis, can be converted into ice M-3,11,2O-triketo-pregnadiene by a novel sequence of chemical reactionsshovvn in the following flow sheet:

CH3 (3H3 5 +=CH C CH; R,- on, 0 -0H, CH 3 /-CH CH OH CHzOHO 10 I II 15 lCH3 CH3 E 3 (EH3 C=O HO-CCH2OH I O -CH3 O: CH

CH CH CH;CHO 'CH2CHO IV III i V VI wherein R represents a substituentconvertible to a keto group by acid hydrolysis, and R represents a ketoor a hydroxyl group.

In this sequence of reactions the starting material, Compound I, isfirst treated with an oxidizing agent to produce thel-acetaldehydol-keto compound, Compound II. This compound is thenreacted with osmium tetroxide and the resulting osmate ester hydrolyzedto convert the methallyl substituent at position 2 to a 5,dihydroxyisobutyl substituent, thereby producing Compound III. Uponreaching Compound III With periodic acid the fl,'y-dihydroxyisobutylsubstituent is converted to an B-ketopropyl group to produce CompoundIV. The ring closure of Compound IV to form the five membered D ring ofthe steroid molecule is effected by reacting this compound with analkali to produce Compound V. Upon hydrolyzing Compound V with acid, theethylenedioxy group is cleaved forming a keto group at position 3 andcausing the double bond to shift from the 5,6 position to the4,5-position, thereby producing Compound VI.

Alternatively, as indicated in the fiowsheet above, Compound IV can beprepared directly from Compound II. In this method Compound II isreacted with ozone and. the resulting ozonide reduced to obtain CompoundIV.

dione wherein the 7-keto substituent is replaced by a cyclic group ofthe formula wherein R represents a hydrocarbon radical or hydrogen, Xrepresents oxygen or sulfur, and n represents the integer 0 or 1, aremost suitable for use as starting materials in our process. having acyclic ketal, mercaptol or hemithioketal group that might be mentionedare 2,4b-dimethyl-l-(fi-hydroxyethyl) 2 methallyl 7 ethylenedioxyl,2,3,4,4a,4b, 5,6,7,8,10,l0a dodecahydrophenanthrene 4 ol, 2,4b-

dimethyl 1 ()8 hydroxyethyl) 2 methallyl 7 eth- September 17, 1952, nowPatent 2,786,064. The 2,4b--

dimethyl 1 9 hydroxyethyl) 2 methallyl 7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one can beprepared by subjecting 2,4b dimethyl 1 (2 tosyloxyethyl) 2 methallyl-Examples of such compounds 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0,10adodecahydrophenanthrene (prepared as described in copending applicationSerial No. 310,134, now Patent 2,786,064) to alkaline hydrolysis. The2,4b-dimethyl-l-(fi-hydroxyethyl) 2 methallyl 7 ethylenemercaptol1,2,3,4,4a, 4b,5,6,7,8,l0,l0a dodecahydrophenanthrene 4 01 and 2,4bdimethyl 1 (fl hydroxyethyl) 2 methallyl- 7 ethylenehemithioketall,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol can be obtainedby reacting 2,4b dimethyl 1 (B hydroxyethyl) 2 methallyll,2,3,4,4a,4b,5,6,7,9,10,102. dodecahydrophenanthrene-4-ol-7-one(prepared as described in copending application Serial No. 310,134, nowPatent 2,786,064) with ethanedithiol and fi-mercaptoethanol respectivelyin the 'presence of fused zinc chloride and anhydrous sodium sulfate.Similarly, the corresponding 4-one compounds can be prepared utilizingthe 4,7-di0ne as the starting material. Although, as indicated above,various substituents can be used to block or protect the 7-keto group,

we have found that the cyclic ketal derivatives, and in particular the7-ethylenedioxy derivatives, are most conveniently utilized as thestarting material in the processes of our invention.

The ethylenedioxy group of the intermediate products formed in ourprocess, namely, Compounds II, III, and

heating with perchloric acid, to produce the corresponding 7-ketocompounds. In this hydrolysis, the double IV, is cleaved by hydrolysiswith acid, for example by bond at the 8az9 position is shifted to the8:8a position, thus forming an a,B-unsaturated ketone.

For the purpose of providing a better understanding of this invention,our processes can be exemplified by the application to a specificstarting material, the ethylenedioxy derivative of2,4b-dimethyl-2-methallyl-1-(,8-hy droxyethyl)1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene-4-ol-7-one.

In the first step of our process, this starting material, 2,4b dimethyl7 ethylenedioxy 2 methallyl 1- (B hydroxyethyl)1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol is reactedwith an oxidizing .agent to convert the 4-hydroxy substituent to a ketogroup and to convert the fl-hydroxyethyl to the acetalde- 'hydosubstituent. We have found that this oxidation is most convenientlyaccomplished by reacting a solution of the starting material in anorganic base with a complex formed by reacting an organic base withchromium trioxide, for example the pyridine-chromium trioxide complex.This method of oxidizing primary and secondary alcohols to thecorresponding carbonyl compounds is described in the copendingapplication of one of us, Serial No. 292,985, filed June 11, 1952. Thus,this oxidation is readily efiected by intimately contacting a solutionof the starting compound in pyridine with the complex formed by reactingchrominum trioxide with pyridine and allowing the reacting mixture tostand at room temperature for suflicient time to complete the oxidation.The 2,4b dimethyl 7 ethylenedioxy 2 methallyl- 1 acetaldehydol,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one is recoveredby diluting the reaction mixture with water, extracting the aqueoussolution with a water immiscible solvent for the product, such as ethylether, chromatographing the resulting ether solution over acid-Washedalumina, and eluting the product with a mixture of petroleum ether andethyl ether.

Although the principal product of the oxidation reaction is 2,4bdimethyl 7 ethylyenedioxy 2 methallyl l acetaldehydol,2,3,4,4a,4h,5,6,7,8,10,10a dodecahydrophenanthrene-4-one, smallamounts of other oxidation products such as 2,4b-dimethyl-7ethylenedioxy2 methallyl 1 8 hydroxyethyl) l,2,3,4,4a, 4b,5,6,7,8,10,l0adodecahydrophenanthrene 4 one and the corresponding l-(carhoxymethyl)compound are also obtained. These products can be reduced by reac tionwith lithium aluminum hydride to produce an epimeric form of thestarting material. This epimeric form of the starting material can beused in the present process as effectively as the original startingcompound, thereby increasing the final yield of product.

In the next steps of our process, the 2-methallyl substituent of2,4bdimethyl-7ethylenedioxy-Z-methallyl-l-acetaldehydo1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one is convertedto a j3-ketopropyl group. As indicated on the flow sheet shown above,this can be accomplished by either direct oxidation, or by cleavage ofthe intermediate glycol (Compound III).

In carrying out this conversion by the direct oxidation, the 2,4bdimethyl 7 ethylenedioxy 2 methallyl- 1 acetaldehydo1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one is dissolvedin a suitable solvent, such as a lower aliphatic alcohol, the solutioncooled to a low temperature of about C., and ozom'zed oxygen containingone equivalent of ozone based on the dimethyl 7 ethylenedioxy 2(5ketopropyl) 1 acetaldehydo 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one is readily recovered by concentrating thereaction mixture under diminished pressure, extracting the concentratewith ether, chromatographing the conasegooa Ind M centrate over acidwashed alumina, eluting with a mixture of petroleum ether-ethyl ether,and evaporating the resulting eluate.

Alternatively, and in accordance with a preferred embodiment of ourinvention, the fi-ketopropyl compound is obtained by a two step processinvolving treating the methallyl compound with osmium tetroxide anddecomposing the resulting osmate ester to produce the corresponding2-'(,B,'y-dihydroxyisobutyl) compound, and cleaving this latter productby treatment with periodic acid. In this procedure, the 2,4b dimethyl 7ethylenedioxy 2- methallyl 1 acetaldehydo1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one is reactedwith osmium tetroxide to form the corresponding osmate ester, thereaction being preferably effected in a suitable inert solvent mediumsuch as benzene, ethyl ether, tetrahydrofuran, and the like, or in amixture of such solvents. The reaction is completed by allowing thereaction mixture to stand at room temperature for about one hour. Theosmate ester is then decomposed by adding ethanol and treating theresulting solution with an aqueous solution of sodium sulfite. Theglycol formed in this reaction mixture can be recovered by filtering theresulting reaction mixture, concentrating this solution under diminishedpressure, extracting this concentrate with chloroform, and evaporatingthe chloroform extract.

The 2,4b dimethyl 7 ethylenedioxy 2 (13, dihydroxyisobutyl) 1acetaldehydo 1,2,3,4,4a,4b,5,6, 7,8,10,10a-dodecahydrophenanthrene-4-oneis then conveniently converted to the corresponding 2-(,8-ketopropyl)compound by reacting a solution of this product in a mixture oftetrahydrofuran and pyridine with a solution of periodic acid andallowing the resulting reaction mixture to stand at about roomtemperature for about onehalf hour. At this point, the mixture isdiluted with water and the tetrahydrofuran removed by concentrationunder diminished pressure. The resulting concentrate is then extractedwith benzene and the 2,4b-dimethyl-7- ethylenedioxy 2 (B ketopropyl) 1acetaldehydo- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one obtained by concentration of the benzene extracts.

The Z-(fl-ketopropyl) compound is then reacted with an alkaline reagentto effect ring closure and form the corresponding steroid compound.Thus, on heating a suspension of 2,4b dimethyl 7 ethylenedioxy 2- (pketopropyl) 1 acetaldehydo 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one in an aqueous solution ofpotassium hydroxide at about 100 C. for nineteen hours A 3 ethylenedioxypregnadiene- 11,20-dione is formed. This product is readily recoveredfrom the resulting alkaline solution by extraction with a suitable waterimmiscible solvent for the product such as chloroform, and concentrationof the resulting solvent extracts.

The 3-ethylenedioxy compound so obtained is hydrolyzed by heating withacids to produce M -pregnadiene- 3,11,20-trione.

The derivatives of A -pregnadiene-il1,20-trione, wherein the 3-ketogroup is protected by a group con vertible to keto by hydrolysis withacid, obtained in accordance with the present invention are valuablecompounds useful as intermediates in the synthesis of cortisone. Thus,for example, dl-A -3-ethylenedioxy-preg nadiene-11,20-dione can beselectively hydrogenated by reaction with hydrogen in the presence ofRaney nickel catalyst to produce dl-A -3-ethylenedioxy-pregnene-11,20-dione by the method shown Berichte 72, 182 for reducing A-3-hydroxy-2O-keto pregnadiene to A -3-hydroxy- 20-keto-pregnene. Thedl-A -3-ethylenedioxy-pregnene- 11,20-dione can then be converted tocortisone by the methods described in the Journal of the AmericanChemical Society 74, 4974 (1952).

The 2,4b dimethyl 1 (,8 hydroxyethyl) 2 methallyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol used as thestarting material in the examples illustrating the processes of thisinvention, can be prepared as described in copending application, SerialNo. 310,134, filed September 17, 1952, now Patent 2,786,064.

EXAMPLE 1 2,4b dimethyl 7 ethylenedioxy 2 methallyl 1 acetaldehydo1,2,3,4,4a,4b,5,6,7,8,10,10 dodecahydrophenanthrene-4-one To the complexfrom 380 mg. of chromium trioxide dissolved in 3.5 cc. of pyridine wasadded 384 mg. of 2,4b dimethyl 7 ethylenedioxy 2 methallyl 1- (,8hydroxyethyl) 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-olin 3 cc. of pyridine. After standing overnight at room temperature, thereaction mixture was diluted with water and extracted with ether. Thecombined ether extracts were washed with water, dried and concentrated.The resulting crude crystalline product was chromatographed on 12 g. ofacid-washed alumina. With petroleum ether-ether there was eluted first2,4b dimethyl 7 ethylenedioxy 2 methallyl- 1 acetaldehydo1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one melting at148-450 C. after recrystallization from other followed by 2,4b-dimethyl-7 ethylenedioxy 2 methallyl 1 (p hydroxyethyl)-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4- one, MP. 1826 C.from ether. Further elution with methanol gave 2,4b dimethyl 7ethylenedioxy 2- methallyl 1 carboxymethyl l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one melting at 215-216 C. afterpurification by recrystallization from ethyl acetate.

The above 1- (ti-hydroxyethyl) compound and the 1(carboxymethyl)compound may be reduced with lithium aluminum hydride in tetrahydrofuranto produce the C11 epimer of 2,4b dimethyl 7 ethylenedioxy- 2 methallyl1 (B hydroxyethyl) 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol, the original starting material.

The 2,4b dimethyl 7 ethylenedioxy 2 methallyl- 1 acetaldehydo1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one on acidhydrolysis yields 2,4bdimethyl 2 methallyl 1 acetaldehydo 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4,7-dione.

Similarly, on acid hydrolysis 2,4b-dimethyl-7-ethylenedioxy 2 methallyl1 ([3 hydroxyethyl) 1,2,3,4, 4a,4b,5,6,7,8,10,l0adodecahydrophenanthrene 4 one and 2,4b dimethyl 7 ethylenedioxy 2methallyl- 1 carboxy methyl 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4 one yields 2,4b -dimethyl- 2 methallyl 1 (5hydroxyethyl) 1,2,3,4,4a,4b,5,6, 7,9,10,10a dodecahydrophenanthrene 4,7dione and 2,4b dimethyl 2 methallyl 1 carboxymethyl 1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene 4,7- dione respectively.

EXAMPLE 2 2,4b dimethyl 7 ethylenedioxy 2 methallyl 1- carboxymethyl1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrop/1enanthrene-4-0ne In anotherexperiment carried out as described in Example 1, the combined etherextracts were extracted with aqueous sodium hydroxide solution at thispoint to remove the carboxymethyl compound before chromatographing themixture. The sodium hydroxide extract was then acidified with aqueoussodium dihydrogen phosphate solution whereupon crystalline2,4b-dimethyl-7-ethylenedioxy 2 methallyl 1 carboxymethyl 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one separated from thesolution.

Chromatography of the ether extracts was then carried out as describedin Example 1 with the exception that the methanol elution was omitted.

7 EXAMPLE 3 To a solution of 145 mg. of 2,4b-dimethyl-7-ethylene- Idioxy 2 methallyl l acetaldehydo 1,2,3,4,4a,4b,5,

6,7,8,10,la dodecahydrophenanthrene 4 one in 1.5 cc. of benzene and 0.5cc. of tetrahydrofuran was added 110 mg. of osmium tetraoxide. After onehour at room temperature the precipitated osmate ester was dissolved in6.5 cc. of ethanol and treated with a solution of 700 mg. of sodiumsulfite in 4 cc. of water. The mixture was agitated thoroughly fortwenty minutes to efiect hydrolysis of the osmate ester. After standingbriefly the upper layer was decanted and the lower layer was washedrepeatedly by decantation with ethanol. The organic solutions werecombined and concentrated to a small volume. Extraction with chloroformfollowed by washing with Water, drying and concentration yieldedcrystalline 2,4b dimethyl 7 ethylenedioxy 2 ([3 "y dihydroxyisobutyl) lacetaldehydo 1,2,3,4,4a,4b,5,6,7, 8,10,10a dodecahydrophenanthrene 4one, melting at 174177 C. After purification by recrystallization frombenzene.

Upon hydrolysis with acid, 2,4b-dimethyl-7-ethylenedioxy 2 (5,dihydroxyisobutyl) 1 acetalde'hydo- 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4- one is converted to 2,4b dimethyl 2 8,dihydroxyisobutyl) 1 acetaldehydo 1,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-4,7-dione.

EXAMPLE 4 2,4b dimethyl 7 ethylenedioxy 2 (6 ketopr0pyl)- 1 acetaldehydo1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrenel-one To 200 mg. of2,4b-dimethyl-7-ethylenedioxy-2-([3, dihydroxyisobutyl) l acetaldehydo1,2,3,4,4a,4b,'5,6, 7,8,10,10a dodecahydrophenanthrene 4 one in 1.5 cc.of tetrahydrofuran and 0.5 cc. of pyridine was added a solution of 152mg. of periodic acid in 1 cc. of water.

The reaction mixture was allowed to stand at room temperature thirtyminutes and then was diluted with Water.

Tetrahydrofuran was removed under vacuum and the u product was extractedwith benzene. The benzene extract was Washed with water, dried andconcentrated to give crystalline 2,4b dimethyl 7 ethylenedioxy 2-ketopropyl) 1 acetaldehydo 1,2,3,4,4a,4b,5,6,7,8,10,lOa-dodecahydrophenanthrene-4-one. The pure material melted at13l133 C. after being recrystallized from ether.

Upon hydrolysis with acid, 2,4b-dimethyl-7-ethylenedioxy 2 ([3ketopropyl) l acetaldehydo 1,2,3,4, 4a,4b,5,6,7,8,l0,l0adodecahydrophenanthrene 4 one is converted to2,4b-dimethyl-2-(fi-keto-propyl)-l-acetaldehydo1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene-4,7-dione.

EXAMPLE 5 dl-A -3-ethylenedioxy-pregnadiene-11,20-di0ne Forty-threemilligrams of 2,4b-dimethyl-7-ethylenedioxy 2 B ketopropyl 1acetaldehydo 1,2,3,4,4a,4b, 5,6,7,8,l0,10a dodecahydrophenanthrene 4 onewas suspended in 10 cc. of 2.5% potassium hydroxide solu- .tion. Thereaction mixture was sealed from the atmosphere under slight vacuum andheated on the steam cone After cooling the reaction mixture wasextracted with chloroform and the extract was dried and concentrated.The residue was recrystallized from ether giving dl-A-3-ethylenedioxy-pregnadiene-l1,20- dione melting at 193-197 C.

When A 3 ethylenedioxy pregnadiene 11,20- dione is hydrolyzed bytreatment with acid, M -pregnadiene-3,11,20-trione is obtained.

Various changes and modifications in the procedure .herein disclosedwill occur to those skilled in the art, and

to the extent that such changes and modifications are embraced by theappended claims, it is to be understood that they constitute part of ourinvention.

What is claimed is: r

l. 2,4b dimethyl 1 acetaldehydro 2 methallyl 7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one.

2. 2,4b dimethyl 1 acetaldehydo 2 methallyl 1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene-4,7- dione.

No references cited.

1. 2,4B - DIMETHYL - 1 - ACETALDEHYDRO - 2 - METHALLYL - 7ETHYLENEDIOXY - 1,2,3,4,4A,4B,5,6,7,8,10,10A-DODECAHYDROPHENANTHRENE-4-ONE.